WO2002002503A1 - Process for preparation of terbinafine and its hydrochloride as an antifungal agent - Google Patents

Abstract

The present invention provides a novel process for preparing terbinafine represented by the formula (I) and its hydrochloride salt represented by the formula (Ia), which show broad spectrum inhibiting activities against squalene epoxidase of fungus and thus are useful as anti-fungal agents. The process of the present invention can produce terbinafine and its hydrochloride salt in a good yield (about from 60 to 80%) and with a high purity by using a palladium catalyst system effectively at each reaction step, thereby carrying out the process effectively in one reactor within a relatively short time.

Description

Process for Preparation of Terbinafine and Its Hydrochloride as an Antifungal Agent

Field of the Invention

The present invention relates to a novel process for preparing terbinafine of the following formula (I) and its hydrochloride salt of the following formula (la). More particularly, it relates to a process for preparing terbinafine and its hydrochloride salt which show inhibiting activities against squalene epoxidase of fungus and thus are useful as an anti-fungal agent.

(I) (la)

Background of the Invention

Terbinafine is an antifungal agent, which acts as an inhibitor against squalene epoxidase of fungus, and it may be administrated orally and has little toxicity. It has been first synthesized by Sandoz Ltd. (Switzerland) in 1980. Until recently, numerous processes for manufacturing terbinafine and its hydrochloride salt have been developed. For example, Korean patent laid-open Nos. 97- 61855(Kim et al.) and 97-6278(Kim et al.), European patent Nos. 24,587(Anton) and 421,302(Susumu et al.), U.S. patent Nos. 4,755,534(Anton) and 5,817,875(Khashayar et al.), J. Med. Chem. 27, 1539(1984), Angew. Chem. Int. Ed. Engl, 26, 320(1987), Tetrahedron Lett., 29, 1509(1988), Tetrahedron Lett, 32, 6109(1996), Tetrahedron Lett., 37, 57(1996), and Bull. Korean Chem. Soc, 1,8, 1218(1997), etc, has disclosed processes for preparing terbinafine and its derivatives. These processes for producing terbinafine and its derivatives may be summarized into four as follows:

In the first method, disclosed in European patent No. 24,587 and U.S. patent No. 4,755,534, N-methyl-1-naphthalenemethanamine is coupled with an en-yne derivative as depicted in Reaction Scheme 1. This method has some drawbacks such as use of reagents which are difficult to treat on the spot of industry and use of starting material which are complicated to prepare due to multiple steps of preparing process. In addition, it is difficult to control the production ratio of cis-isomer to trans-isomer(l :3). The mixture of cis- and trans- isomer of terbinafine is obtained, which results in its difficult resolution. Reaction Scheme 1

Terbinafine

Terbinafine

In the second method, described in European patent No. 24,587, Korean patent laid-open Nos. 97-61855 and 97-6278, en-yne structure is selectively induced by reduction reaction of diacetylene(diyne) as depicted in the Reaction Scheme 2. This method may selectively introduce a trans isomer of en-yne structure into terbinafine, but it has a drawback of using a strong reducing agent such as LiAlH₄(LAH) and i-Bu₂AlH(DIBAL-H) etc. Reaction Scheme 2

Terbinafine

CH₃ 1) CuCI 2) Reducing agent

Br-≡≡- -j-CHa Terbinafine

OH CH₃ 3) MsCI

CH₃ 1) Pd (0) 2) DIBAL

^=^_ H-≡- H-CHs __ Terbinafine

OH

In the third method, disclosed in U.S. patent No. 5,817,875, it has advantages such as use of relatively simple reaction condition and of economic reagents. However, this method has no selectivity when the dehydration is carried out. As a result, (E)-form of terbinafine is obtained with at most 50%. The reaction is illustrated in Reaction Scheme 3. Reaction Scheme 3

Terbinafine

In the fourth method, disclosed in European patent No. 421.302, N- methyl-1- naphthalenemethanamine is reacted with (E)-l,3-dichloropropene in aprotic polar solvent such as DMSO in the presence of a base such as K CO₃ for about 6 hours to obtain (E)-N-(3-chloro-2-propenyl)-N-methyl-l- naphthalenemethanamine, and then reacted with 3,3-dimethyl-l-butyne in a solvent of THF in the presence of n- butylamine with a catalyst of tetrakis(triphenylphosphine) palladium for about 17 hours to obtain (E)- terbinafme.

This method may prepare an en-yne structure in a pure (E) form by using a relatively simple reaction condition. However, this method has some drawbacks since it uses an expensive (E)-l,3-dichloropropene, the reaction be carried out in two steps, and in hours of the reaction time is too long in the synthesis of en-yne structure by using a catalyst of tetrakis(triphenyl phosphine)palladium, thereby rendering a side reaction. The reaction is depicted in Scheme 4. Reaction Scheme 4

Terbinaf ine

(PPh₃)₄Pd / Cul n-BuNH₂ / 17hr

Detailed description of the Invention

The present inventor have extensively studied to solve the above problems and to obtain a higher yield of terbinafine than that of a conventional method. As a result, it has been found that the reaction time in the synthesis of en-yne structure of terbinafine may shorten to 30 to 60 minutes by using (PhCN)₂ PdCl₂ as a palladium catalyst in the presence of piperidine [Tetrahedron Lett., 32, 6109(1991)and Tetrahedron Lett., 37,57 (1996)], and the reaction of N-methyl-1- naphthalenemethanamine and 1,3-dichloropropene to obtain N-(3-chloro-2- propenyl)-N-methyl-l naphthalenemethanamine may be not only accelerated with a SN₂-typed reaction mechanism as described in European patent No. 421 ,302, but also with a formation of allyl-palladium complex by using 1,3- dichloropropene in the presence of palladium catalyst.

It has been also found that the above reaction using a palladium catalyst may produce N-(3-chloro-2-propenyl)-N-methyl-l-naphthalenemethanamine having more trans-form than cis-form (up to 85% of trans-form) by its isomerism of the double bond when 1,3-dichloropropene (1:1 of cis to trans) is reacted with N-methyl-1 -naphthalenemethanamine or its hydrochloride salt under non- polar solvent such as hexane, petroleum ether, cyclohexane, toluene, benzene, ethyl acetate, ethyl ether, isopropyl ether or tetrahydrofuran, in the presence of base such as triethylamine.

Based on these studies, the present inventors have developed a new process for preparing terbinafine with high purity and high yield, which comprises using a palladium catalyst from the beginning of the reaction in the non-polar solvent and using N-methyl-1 -naphthalenemethanamine or its hydrochloride salt, 1 ,3-dichloropropene (1 : 1 of cis to trans) as starting materials in one reactor, instead of producing N-(3-chloro-2-propenyl)-N-methyl-l- naphthalenemethanamine by a SN₂ typed displacement reaction of N- methyl- 1- naphthalenemethanamine and (E)-l,3-dichloropropene in aprotic polar solvent. The present inventors have completed the present invention based on these findings.

The present invention is to selectively produce trans-isomer of N-(3- chloro-2-propenyl)-N-methyl-l -naphthalenemethanamine represented by the following formula (II) by reacting N-methyl-1 -naphthalenemethanamine or its hydrochloride salt and 1,3-dichloropropene (1:1 of cis to trans) as starting materials in an aprotic non-polar solvent in the presence of a base and 0.1 to 5 mol% of a palladium (0) catalyst at 0 to 50^°C for 1 to 6 hours, and then produce (E)-terbinafine represented by the following formula (I) and its hydrochloride salt represented by the following formula (la) by using from 0.1 to 5 mol% of a palladium (II) catalyst in the above reaction medium followed by adding sequentially cupper iodide (Cul) in catalytic amount, amine, and 3,3-dimethyl-l- butyne.

(I) da) (II)

Best Mode for Carrying Out the Invention

(E)-terbinafine according to the present invention is prepared as depicted in Reaction Scheme 5: Reaction Scheme 5

_*■ Terbinafine

Pd(ll) Cul / amine

According to the above Reaction Scheme 5, N-(3-chloro-2-propenyl)-N- methyl-1 -naphthalenemethanamine represented by the formula (II) is prepared by the process, which comprises dissolving N-methyl-1 -naphthalenemethanamine or its hydrochloride salt in a non-polar solvent, and then reacting with 1,3- dichloropropene (1 : 1 of cis to trans) in the presence of a tertiary amine such as triethylamine(Et N), or an inorganic base having no substitutional nucleophilicity such as K₂CO , and a palladium(O) catalyst as shown in Reaction Scheme 6 (up to 85% of trans-form), wherein 1: 1 of equivalent ofN-methyl-1- naphthalenemethanamine and 1,3-dichloropropene is used. Reaction Scheme 6

(trans)-(E)-form (cis)-(Z)-form

Maximum 85 15

In the above Reaction Scheme 6, reaction temperature is usually in a range of from 0 to 50^°C , but it is more preferable in a range of 0^°C to ambient temperature.

As a palladium catalyst, tetrakis(triphenyIphosphine) palladium [(PPh₃)₄Pd] is used as a Pd(0) catalyst, and bis(triphenylphospl ine)palladium dichloride[(PPh₃)₂PdCl₂], or bis(benzonitrile)palladium dichloride[(PhCN)₂PdCl₂] is used as a Pd(II) catalyst. In the above Reaction Scheme, it is preferable to use tetrakis(triphenylphosphine) palladium[(PPh )₄Pd] as a Pd(0) catalyst. The reactivity of the catalysts is in order of (PPh₃)₄Pd » (PPh₃)₂PdCl₂ » (PhCN)₂PdCl₂. The reaction time is usually about 1 to 2 hours at 0^°C, and about 1 to 4 hours at room temperature on using (PPh₃)₄Pd, about 5 hours at room temperature on using (PPh₃)₂PdCl₂, and about at least 48 hours at room temperature on using (PhCN)₂PdCl₂. If no catalyst is used in the above reaction, the reaction cannot be carried out under the above condition. The amount of the catalyst is preferably from 0.1 to 5 mol%. If the catalyst is used less than 0.1 mol%, the reaction time is too long, and if it is used over 5 mol%, the cost may be increased.

The amount of the base is 1 to 1.5 equivalent based on N-methyl-1- naphthalenemethanamine when N-methyl-1 -naphthalenemethanamine is used as a free form, while the amount of the base is 2 to 2.5 equivalents based on N-methyl- 1 -naphthalenemethanamine when said compound is used as its hydrochloride salt form.

The solvent is used with 5 to 20 times based on N-methyl-1 - naphthalenemethanamine. It is preferable to use 10 times based on said compound. Furthermore, in the above Reaction Scheme 6, when (PPh₃)₄Pd is used as a catalyst, and an inexpensive 1,3-dichloropropene (1:1 of cis to trans) instead of an expensive (E)-l,3-dichloropropene is used, a trans isomer of N-(3-chloro-2- propenyl)-N-methyl-l-naphthalenemethanamine(up to 85% of trans-form) is mainly produced, wherein the reaction is rapidly carried out even at 0 to 50^°C thus, in accordance with the present invention, it is possible to provide (E)- terbinafine by using an inexpensive 1,3-dichloropropene (1:1 of cis to trans) as a starting material.

To the above reaction solution of the resulting N-(3-chloro-2-propenyl)- N-methyl-1 -naphthalenemethanamine is added (PhCN)₂PdCl₂ or (PPh₃)₂PdCl₂ as a catalyst and about 0.1 to 5 mol% of Cul, and simultaneously added an amine and 3,3-dimethyl-l-butyne to produce (E)-terbinafine as shown in Reaction Scheme 7, wherein the coupling reaction in the trans form is more rapid than that in the cis form. The amine is preferable to use a piperidine in the amount of 1 to 10 equivalents and 3,3-dimethyl-l-butyne is used about 0.85 to 1 equivalent, based on N-methyl-N-(3-chloro-2-propenyl)-naphthalenemethanamine. Reaction Scheme 7

Cul / amine Pd(N) catalyst

trans : cis = 85 : 15

Terbinafine

In the Reaction Scheme 1, the reactivity of palladium catalysts depends on the kind of amine and their ligand. The reactivity is in order of (PhCN)₂PdCl₂ : piperidine(l to 10 equivalents) » (PPh₃)₂PdCl₂ : n-BuNH₂(2 equivalents) » (PPh₃)₄Pd : n-BuNH₂(2 equivalents). The reaction time is from 1 to 4 hours when (PhCN)₂PdCl₂ is used; from 8 to 10 hours when (PPh₃)₂PdCl₂ is used; and at least 72 hours when (PPh₃)₄Pd is used. In addition, no side reaction is occurred when (PhCN) PdCl₂ is used, but it is observed a side reaction when (PPh₃)₂PdCl₂ and (PPh₃)₄Pd are used. By using the difference of the reactivity of the catalyst, (E)-terbinafine may be obtained by participating solely a trans form of N-(3-chloro-2-propenyl)-N-methyl-l- naphthalenemethanamine in the reaction. A cis-form of N-(3-chloro-2-propenyl)- N-methyl-1 -naphthalenemethanamine remains unreacted. Instead, only a small amount of (Z)-terbinafme is produced. Thus, when the terbinafine is converted into its hydrochloride salt, its purification is very easy.

The present invention is to use and choose the most suitable catalyst at each reaction step according to the difference of catalytic reactivity as shown in Reaction Scheme 8. Reaction Scheme 8

Terbinafine

(PhCN)₂PdCI z Cul / amine

As shown above, the first step uses (PPh₃)₄Pd, and the second step uses (PhCN)₂PdCl₂ as a catalyst. The amount of the catalyst in each step is respectively from 0.1 to 5 mol%, and preferable from 0.5 to 2 mol%. The reaction time of each reaction step is from about 1 to about 2 hours at 0^°C or about 1 to 4 hours at room temperature when 1,3-dichloropropene is used. Thus, the whole reaction according to the present invention may be completed in relatively short time. In the first step of the above Reaction Scheme, a tertiary amine such as triethylamine, or an inorganic base having no substitutional nucleophilicity such as K₂CO₃ may be used as a base. In the coupling reaction of the second step, piperidine may be used as an amine.

The resulting crude (E)-terbinafine may be easily purified (synthesized) to its pure hydrochloride salt in a conventional manner (J. Med. Chem., 27(12), 1539(1984))

The present invention will be more fully understood by the following examples which illustrate the invention, but are not construed to be limited thereto.

Example 1: Preparation of N-(3-chloro-2-propenyl)-N-methyl-l- naphthalenemethanamine

(a) Use of catalyst, (PPh₃)₂PdCl₂ 34.3 g of N-methyl-1 -naphthalenemethanamine (or its hydrochloride salt), 30.3g of Et₃N, and 24.7ml of 1,3-dichloropropene were dissolved in 300ml of tetrahydrofuran (THF), and 7g of (PPh₃)₂PdCl₂ were then added thereto under nitrogen atmosphere. The resulting mixture was stirred for 4 hours at room temperature. Upon completion of reaction, the reaction mixture was extracted with aqueous saturated NH₄C1 solution and ethylacetate. The organic layer was dried over anhydrous MgSO₄. The solvent was distilled off under vacuum, and then purified by a column chromatography on silica gel. 44.09g (yield: 89.7%) of the object compound (47 : 53 of cis to trans) were obtained as oil. -Cis isomer: 1H NMR(CDC1₃) δ 7.40~8.30(m, 7H), 6.19(d, 1H, j=7.2Hz).

5.97(q, 1H), 3.92(s, 2H), 3.33(d, 2H), 2.26(s, 3H)

-Trans isomer: 1H NMR(CDC1₃) δ 7.40~8.30(m, 7H), 6.0~6.2(m, 2H). 3.90(s, 2H), 3.10(d, 2H), 2.24(s, 3H)

(b) Use of catalyst, (PhCN)₂PdCl₂

34.3g of N-methyl-1 -naphthalenemethanamine (or its hydrochloride salt), 30.3g of Et₃N, and 24.7ml of 1,3-dichloropropene were dissolved in 300ml of THF, and 3.8g of (PhCN) PdCl₂ were then added thereto under nitrogen atmosphere. The resulting mixture was stirred for 48 hours at room temperature. Upon completion of reaction, the reaction mixture was extracted with saturated aqueous NH₄C1 solution and ethylacetate. The organic layer was dried over anhydrous MgSO₄. The solvent was distilled off under vacuum, and then purified by a column chromatography on silica gel. 36.21g (yield: 73.5%) of the object compound (49 : 51 of cis to trans) were obtained as oil.

(c) Use of catalyst, (PPh₃)₄Pd

(o-l)

34.3g of N-methyl-1 -naphthalenemethanamine (or its hydrochloride salt),

30.3g of Et₃N, and 24.7ml of 1,3-dichloropropene were dissolved in 300ml of THF, and 11.5g of (PPh₃) Pd were then added thereto under nitrogen atmosphere. The resulting mixture was stirred for 2 hours at 0^°C (optionally, 4 hours at room temperature). Upon completion of reaction, the reaction mixture was extracted with aqueous saturated NH₄C1 solution and ethylacetate. The organic layer was dried over anhydrous MgSO₄. The solvent was distilled off under vacuum, and then purified by a column chromatography on silica gel dried under. 45.6 lg

(yield: 92.8%) of the object compound (26 : 74 of cis to trans) were obtained as oil.

On using K₂CO₃, which is an inorganic base having no substitutional nucleophilicity , instead of using Et₃N, the same product may be obtained (yield 77.8%).

(c-2)

The procedure was similar to the above Example (c-1), except that toluene instead of THF was used as solvent. 44.53g (yield: 90.6%) of the object compound (18 : 82 of cis to trans) were obtained as oil. (c-3)

The procedure was similar to the above Example (c-1) except that benzene instead of THF was used as solvent. 44.09g (yield: 89.7%) of the object compound (20 : 80 of cis to trans) were obtained as oil.

(c-4) The procedure was similar to the above Example (c-1) except that ethyl acetate instead of THF was used as solvent. 45.22g (yield: 92.0%) of the object compound (18 : 82 of cis to trans) were obtained as oil.

(c-5)

The procedure was similar to the above Example (c-1) except that isopropyl ether instead of THF was used as solvent. 45.12g (yield: 91.8%) of the object compound (20 : 80 of cis to trans) were obtained as oil.

(c-6)

The procedure was similar to the above Example (c-1) except that ethyl ether instead of THF was used as solvent. 44.82g (yield: 91.2%>) of the object compound (18 : 82 of cis to trans) were obtained as oil. (c-7)

The procedure was similar to the above Example (c-1) except that cyclohexane instead of THF was used as solvent. 45.61g (yield: 93.5%) of the object compound (15 : 85 of cis to trans) were obtained as oil. (c-8)

The procedure was similar to the above Example (c-1) except that hexane instead of THF was used as solvent. 44.68g (yield: 90.9%) of the object compound (19 : 81 of cis to trans) were obtained as oil. (c-9) The procedure was similar to the above Example (c-1) except that toluene was used instead of THF as solvent. 45.41g (yield: 92.4%) of the object compound (17 : 83 of cis to trans) were obtained as oil.

Example 2: Preparation of (E)-terbinafine

(a) Use of catalyst, (PPh₃)₂PdCl₂

34.3 g of N-methyl-1 -naphthalenemethanamine (or its hydrochloride salt), 30.3g of Et₃N, and 24.7ml of 1,3-dichloropropene were dissolved in 300ml of THF, and then 7g of (PPh₃)₂PdCl₂ were then added thereto under nitrogen atmosphere. Upon completion of reaction, the resulting mixture was stirred for 4 hours at room temperature. 3.8g of Cul, 39.5ml of n-BuNH₂, and 37.1ml of 3,3- dimethyl-l-butyne were added to the reaction mixture, and then stirred for 8 hours. Upon completion of reaction, the mixture was then extracted with aqueous saturated NH C1 solution and ethyl acetate. The organic layer was dried over anhydrous MgSO₄, and filtered with silica gel pad. The solvent was distilled off under vacuum, and then purified by a column chromatography on silica gel. 26.52g (yield: 45.5%) of the object compound in the pure (E)-form were obtained as oil.

1H NMR(CDC1₃) δ 7.3~8.3(m, 7H), 6.1~6.2(m, 1H), 5.68(d, 1H, 15Hz), 3.89(s, 2H), 3.13(d, 2H), 2.22(s, 3H), 1.21(s, 9H) (b) Use of catalyst, (PPh₃)₄Pd

34.3g of N-methyl-1 -naphthalenemethanamine (or its hydrochloride salt), 30.3g of Et₃N, and 24.7ml of 1,3-dichloropropene were dissolved in 300ml of THF, and 11.5g of (PPh₃)₄Pd were then added thereto under nitrogen atmosphere. The resulting mixture was stirred for 30 minutes at 0^°C . Upon completion of reaction, 3.8g of Cul, 39.5ml of n-BuNH₂, and 37.1ml of 3,3-dimethyl-l-butyne were added to the reaction mixture, and then stirred for 72 hours at room temperature. Upon completion of reaction, the reaction mixture was extracted with aqueous saturated NH₄C1 solution and ethylacetate. The organic layer was dried over anliydrous MgSO₄. The solvent was distilled off under vacuum, and then purified by a column chromatography on silica gel. 39.75g (yield: 68.2%) of the object compound in the pure (E)-form were obtained as oil.

(c) Use of catalyst, (PhCN)₂PdCl₂ 34.3g of N-methyl-1 -naphthalenemethanamine (or its hydrochloride salt),

30.3g of Et₃N, and 24.7ml of 1,3-dichloropropene were dissolved in 300ml of THF, and 3.8g of (PhCN)₂PdCl₂, were then added thereto under nitrogen atmosphere. The resulting mixture was stirred for 48 hours at room temperature. Upon completion of reaction, 3.8g of Cul, 198ml of piperidine, and 37.1ml of 3,3- dimethyl- 1-butyne were added to the reaction mixture, and then stirred for 30 minutes. Upon completion of reaction, the reaction mixture was extracted with aqueous saturated NH₄C1 solution and ethylacetate. The organic layer was dried over anhydrous MgSO₄. The solvent was distilled off under vacuum, and then purified by a column chromatography on silica gel. 25.47g (yield: 73.5%) of the object compound in the pure (E)-form were obtained as oil.

(d) Sequential use of catalysts, (PPh₃)₄Pd and (PhCN)₂PdCl₂ (d-1)

34.3g of N-methyl-1 -naphthalenemethanamine (or its hydrochloride salt), 30.3g of Et₃N, and 24.7ml of 1 ,3-dichloropropene were dissolved in 300ml of cyclohexane, and 2.3g of (PPh₃)₄Pd were then added thereto under nitrogen atmosphere. The mixture was stirred for 2 hours at 0^°C and then 4 hours at room temperature. Upon completion of reaction, 0.76g of (PhCN)₂PdCl₂, 3.8g of Cul,

198ml of piperidine, and 22.17ml of 3,3-dimethyl-l-butyne were added to the reaction mixture, and then stirred for 4 hours at room temperature. Upon completion of reaction, the reaction mixture was extracted with aqueous saturated

NH₄C1 solution and ethyl acetate, and the organic layer was then washed with

NaHCO₃ solution. The organic layer was dried over anliydrous MgSO₄. The solvent was distilled off under vacuum, and then purified by a column chromatography on silica gel. 45.52g (yield: 78.1%) of the object compound in the pure (E)-form were obtained as oil.

By using K₂CO₃, which is an inorganic base having no substitutional nucleophihcity, instead of using Et₃N, the same product may be also obtained with yield of 61.5%. (d-2)

The procedure was similar to the above Example (d-1) except that toluene instead of cyclohexane was used as solvent. 43.89g (yield: 75.3%) of the object compound in the pure (E)-form were obtained as oil.

(d-3) The procedure was similar to the above Example (d-1) except that benzene instead of cyclohexane was used as solvent. 41.15g (yield: 70.6%) of the object compound in the pure (E)-form were obtained as oil.

(d-4)

The procedure was similar to the above Example (d-1) except that ethyl acetate instead of cyclohexane was used as solvent. 44.82g (yield: 76.9%) of the object compound in the pure (E)-form were obtained as oil.

(d-5)

The procedure was similar to the above Example (d-1) except that isopropyl ether instead of cyclohexane was used as solvent. 41.67g (yield: 71.5%) of the object compound in the pure (E)-form were obtained as oil. (d-6)

The procedure was similar to the above Example (d-1) except that ethyl ether instead of cyclohexane was used as solvent. 44.71g (yield: 76.7%) of the object compound in the pure (E)-form were obtained as oil. (d-7)

The procedure was similar to the above Example (d-1) except that hexane instead of cyclohexane was used as solvent. 43.02g (yield: 93.5%) of the object compound in the pure (E)-form were obtained as oil. (d-8) The procedure was similar to the above Example (d-1) except that petroleum ether instead of cyclohexane was used as solvent. 43.3 lg (yield: 74.3%o) of the object compound in the pure (E)-form were obtained as oil. (d-9)

The procedure was similar to the above Example (d-1) except that THF instead of cyclohexane was used as solvent. 39.34g (yield: 67.5%) of the object compound in the pure (E)-form were obtained as oil.

Example 3 : Preparation of (E)-terbinafine-HCl

(a)

29. lg of (E)-terbinafme as oil were dissolved in 290ml of isopropyl ether, and 40ml of 3N-HCl/MeOH were added to this solution. The solvent was distilled off under vacuum. After isopropyl ether was added to the residue, the residue was filtered and then dried. 30.2g (yield: 92.1%) of the object compound were obtained.

1H NMR(CDC1₃+D₂0) δ 7.5~8.2(m, 7H), 6.37(dt, 1H, 15Hz, 7.5Hz). 5.87(d, 1H, 15Hz), 4.62(s, 2H), 3.72(d, 2H, 7.5Hz), 2.60(s, 3H), 1.23(s, 9H)

(b) 34.3g of N-methyl-1 -naphthalenemethanamine (or its hydrochloride salt) and 24.7ml of 1,3-dichloropropene were dissolved in 300ml of cyclohexane, and 2.3g of (PPh₃)₄Pd were then added thereto under nitrogen atmosphere. The resulting mixture was stirred for 2 hours at 0^°C . Upon completion of reaction, 0.76g of (PhCN)₂PdCl₂, 3.8g of Cul, 198ml of piperidine, and 22.17ml of 3,3- dimethyl- 1-butyne were added thereto, and then stirred for 2 hours at room temperature. Upon completion of reaction, the mixture was extracted with aqueous saturated NH₄C1 solution and ethyl acetate. To the resulting organic layer was added an active carbon, heated for 30 minutes, dried over anhydrous MgSO₄, and then filtered with celite filter. The solvent was distilled off under vacuum, and 540ml of isopropyl ether were added to the residue. Thereafter, 67ml of 3N-HC1 in methanol solution was added to the above mixture, and the resulting solids were filtered to obtain the object compound. 41.09g (yield: 70.5%) of the solid product were obtained.

When compared with the prior art, the present invention has a number of advantages over the conventional processes:

First, in the prior art, the mixture of (E)-terbinafme and (Z)-terbinafme is obtained by synthesizing simultaneously cis- and trans-isomers with en-yne structure. Therefore, in order to obtain a pure (E)-terbinafme, and isolation or a selective reduction reaction of the triple bond into the (E)-terbinafine should be carried out. Furthermore, N-methyl-1 -naphthalenemethanamine and expensive (E)-l,3-dichloropropene are reacted by SN₂-typed substitution reaction for a long time, i.e., 5 hours or more and then purified. Thereafter, the resulting mixture is coupled with 3,3-dimethyl-l-butyne in the presence of (PPh₃) Pd catalyst for over 17 hours. Hence, a lengthy reaction period and two reaction steps are needed to obtain terbinafine in the prior art.

On the contrary, the present invention can produce a pure (E)-terbinafine with a high yield (about 10.5%) in a short time in one reactor by a substitution and coupling reactions, wherein N-methyl-1 -naphthalenemethanamine is reacted with an inexpensive 1 ,3-dichloropropene (1 : 1 of cis to trans) by using a palladium catalyst system to obtain N-(3-chloro-2-propenyl)-N-methy 1-1- naphthalenemethanamine (up to 85% of trans-form), and coupling reaction with 3,3-dimethyl-l-butyne (0.85 to 1 equivalent) is then carried out in the same solvent and palladium catalyst. Second, in the prior art, only a catalyst, (PPh₃)₄Pd is used in the coupling reaction of N-(3-chloro-2-propenyl)-N-methyl-l -naphthalenemethanamine and 3, 3 -dimetyl- 1-butyne. A great deal of catalyst (5 mol % or more) is used in this process. Nevertheless, it has disadvantages such as a lengthy reaction time (about 17 hours) and side reactions. On the contrary, according to the present invention, it is possible to shorten the reaction time to 2 to 4 hours, to reduce an amount of the palladium catalyst up to about 0.7 mol% and to decrease the side reactions by using sequentially the catalyst at each step of substitution and coupling reactions.

Third, according to the present invention, it is possible to obtain a pure (E)-terbinafine with high yield by using an inexpensive 1 ,3-dichloropropene (1:1 of cis to trans) in the presence of palladium catalyst system, whereas only an expensive (E)- 1,3-dichloropropene is used in the prior art.

Fourth, according to the present invention, the purification of the final product can be easily carried out because only a trans-isomer of N-(3-chloro-2- propenyl)-N-methyl-l -naphthalenemethanamine can be converted into (E)- terbinafme and a cis-isomer of said compound can make it remain unreacted by using the difference of the reactivity of a trans-isomer and a cis-isomer of N-(3- chloro-2-propenyl)-N-methyl-l -naphthalenemethanamine and using 0.85 to 1 equivalent of 3.3 -dimethyl- 1-butyne in the presence of (PPh₃)₄Pd and (PhCN)₂PdCl₂ catalysts.

Claims

What is claimed is:

1. A process for producing terbinafine of the following formula (I) and its hydrochloride salt of the following formula (la) in one reactor comprising: selectively preparing a trans isomer of N-(3-chloro-2-propenyl)-N- methyl-1 -naphthalenemethanamine of the following formula (II) by reacting N- methyl-1 -naphthalenemethanamine or its hydrochloride salt with 1,3- dichloropropene in the presence of a base and about 0.1 to 5 mol% of a palladium catalyst [Pd(0)] under a non-polar solvent at the temperature of from 0 to 50^°C; and sequentially adding about 0.1 to 5 mol% of cupper iodide (Cul), a suitable amount of amine, and a suitable amount of 3,3-dimethyl-l-butyne to the mixture in the presence of 0.1 to 5 mol% of a palladium catalyst [Pd(II)].

(I) (la) (II)

2. The process as defined in claim 1, wherein said palladium catalyst [Pd(0)] at the first step is tetrakis(triphenylphosphine) palladium [(PPh₃) Pd], and said palladium catalyst [Pd(II)J at the second step is bis(triphenylphosphine) palladium dichloride[(PPh₃)₂PdCl₂] or bis(benzonitrile)palladium dichloride [(PhCN)₂PdCl₂].

3. The process as defined in claim 1 , wherein said base is a tertiary amine including triethylamine(Et₃N) or an inorganic base having no substitutional nucleophihcity including K₂CO₃.

4. The process as defined in claim 1, wherein said amine is a piperidine used by the amount of 5 to 10 equivalents, and said 3,3-dimethyl-l-butyne is used by the amount of 0.85 to 1 equivalent, these amounts are based on said N-methyl- N-(3-chloro-2-propenyl)-naphthalenemethanamine.

5. The process as defined in claim 1, wherein said non-polar solvent is selected from the group consisting of tetrahydrofuran, ethyl acetate, hexane, petroleum ether, cyclohexane, toluene, benzene, ethyl ether, and isopropyl ether.